The present invention relates to compounds that are shown to be potent cyclin/cyclin dependent kinase (cdk) inhibitors. Compounds with these properties are shown to be potent inhibitors of cell growth and proliferation. Such compounds can be used to treat the following conditions: rheumatoid arthritis, lupus, type I diabetes, multiple sclerosis, cancer, restenosis, gout and other proliferative diseases mediated by elevated levels of cell proliferation compared to a healthy mammal. Compounds of the present invention which are biaryl substituted purine derivatives are shown to be potent antiproliferative agents against a number of human transformed cell lines, and also inhibitors of human cyclin/cdk kinase complexes.
Cellular Proliferation and Cancer
The disruption of external or internal regulation of cellular growth can lead to uncontrolled proliferation and in cancer, tumor formation. This loss of control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Further, although tumor cells can no longer control their own proliferation, they still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
Cyclin Dependent Kinases and Cell Cycle Regulation
Progression of the normal cell cycle from the G1 to S phase, and from the G2 phase to M phase is dependent on cdks (Sherr, C. J., Science 274:1672-1677 (1996)). Like other kinases, cdks regulate molecular events in the cell by facilitating the transfer of the terminal phosphate of adenosine triphosphate (ATP) to a substrate protein. Isolated cdks require association with a second subunit, called cyclins (Desai et al., Mol. Cell. Biol., 15:345-350 (1995)). Cyclins cause conformational changes at the cdk active site, allowing ATP access and interaction with the substrate protein. The balance between its rates of synthesis and degradation controls the level of each cyclin at any point in the cycle (Elledge, S. J., et al., Biochim. Biophys. Acta, 1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cell cycle and cellular transformation are summarized in Table 1.
Abnormal Cyclin/cdk Activity in Cancer
In a normal cell, interlocking pathways respond to the cell""s external environment and internal checkpoints monitor conditions within the cell to control the activity of cyclin/cdk complexes. A reasonable hypothesis is that the disruption of normal control of cyclin/cdk activity may result in uncontrolled proliferation. This hypothesis appears to hold in a number of tumor types in which cyclins are expressed at elevated levels (Table 1). Mutations in the genes encoding negative regulators (proteins) of cyclin/cdk activity are also found in tumors (Larsen, C.-J., Prog. Cell Cycle Res., 3:109-124 (1997)); (Kamb, A., Trends in Genetics, 11:136-140 (1995)). Members of the Cip family of cdk inhibitors form a ternary complex with the cyclin/cdk and require binding to cyclinA, cyclinE, or cyclinD (Hall, M., et al., Oncogene, 11:1581-1588 (1995)). In contrast, Ink family members form a binary complex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; et al., EMBO J., 14:503-511 (1995)).
Inhibitors of Cyclin/cdk Complexes as Potential Anticancer Agents
Tumors with elevated cyclin/cdk activity, whether from the over expression of cyclins or the loss of an endogenous cdk inhibitor, are prime targets for potential therapies based on small molecule cyclin/cdk inhibitors. In fact, several small molecule inhibitors of cyclin/cdks are reported (Meijer, L., et al., xe2x80x9cProgress in Cell Cycle Research,xe2x80x9d Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATP site of the kinase. Some information is known about small molecule inhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J. et al., xe2x80x9cAnn. Rep. Med. Chem.,xe2x80x9d J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 26 (1994)) and tyrosine kinases (Fantl, W. J., et al., Ann. Rev. Biochem., 62:453 (1993); Burke, T. R., Drugs of the Future, 17:119-1131 (1992); Dobrusin, E. M. et al., xe2x80x9cAnn. Rep. Med. Chem,xe2x80x9d J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 18 (1992); Spence, P., Curr. Opin. Ther. Patents, 3:3 (1993)). A number of known inhibitors were obtained from commercial sources or were synthesized by literature procedures.
Purine Compounds as Cyclin/cdk Inhibitors
There are several reports of 2,6-diamino substituted purine derivatives as cyclin/cdk inhibitors and as inhibitors of cellular proliferation. Among those are reports by U.S. Pat. No. 5,583,137 to Coe, et al., olomoucine (Vesely, J., et al., Eur. J. Biochem., 224:771-786 (1994)), roscovitine (Meijer, L., Eur. J. Biochem., 243:527-536 (1997)), WO 97/16452 to Zimmerman, Imbach, P., et al., Bioorg. Med. Chem. Lett., 9:91-96 (1999), Norman, T. C., et al., J. Amer. Chem. Soc., 118:7430-7431 (1996), Gray, N. S., et al., Tetrahedron Lett., 38:1161-1164 (1997), Gray, N. S., et al., Science, 281:533-538 (1998), WO 98/05335 to Lum, et al., Schow, S. R., et al., Bioorg. Med. Chem. Lett, 7:2697-2702 (1997), U.S. Pat. No. 5,886,702 to Mackman, et al., Nugiel, D. A., et al., J. Org. Chem., 62:201-203 (1997), and Fiorini, M. T. et al., Tetrahedron Lett., 39:1827-1830 (1998). Many of these reported compounds are shown to inhibit cyclin/cdk complexes and have modest cellular proliferation inhibition properties.
The compounds of the present invention are shown to have far superior biological activities as cyclin/cdk complex inhibitors as well as inhibitors of cellular proliferation compared to those previously reported. In fact, the art (e.g., Fiorini, M. T. et al., Tetrahedron Lett., 39:1827-1830 (1998)) teaches away from compounds of this invention, claiming lack of cellular proliferation inhibition.
The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds arc useful in inhibiting cellular proliferation in a mammal by administering to such mammal an effective amount of the compound.
In one embodiment, the compounds of the present invention are represented by the chemical structure found in Formula I 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention is directed to a compound of the following formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a first intermediate compound of the formula: 
xe2x80x83where Z=Br or I;
with a compound of the formula: (R2xe2x80x94B(OH)2) or (R2xe2x80x94Sn(n-Bu)3 or R2xe2x80x94SnMe3), or
mixtures thereof, under conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a compound of the formula: 
xe2x80x83under reductive or hydrogenation conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a first intermediate compound of the formula: 
with a compound of the formula: 
where V1=
NH2;
OH; or
SH;
under conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=
NR1C(O)R3;
NR1C(O)R5;
NR1SO2R3;
NR1C(O)NHR3; or
NR1C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof; said process comprising:
reacting a first intermediate compound having the same formula as the purine derivative compound except that Y=NHR1, with R3COCl or R5COCl or R3SO2Cl or R3NCO or R6OC(O)Cl under conditions effective to form the purine derivative compound.
Yet another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
V=
NH;
O;
S; or
CH2;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-1-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=
CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=NHC(O)CH(R6)NH2 
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R7 is a heterocycle selected from the group consisting of:
thiophene;
furan;
pyrrole;
thiazole;
pyrazole;
imidazole;
isoxazole;
isothiazole; and
1,3,4-thiadiazole;
or a pharmaceutically acceptable salt thereof; said process comprising:
reacting a first intermediate compound having the same formula as the purine derivative compound except that Y is NH2, with a compound of the formula: PNHCH(R6)CO2H under conditions effective to form the purine derivative compound after a suitable deprotection strategy,
wherein
P=
C(O)OtBu;
C(O)OCH2Ph;
9-Fluorenylmethyl Carbamate (Fmoc);
Benzyl; or
Allyl Carbamate (Alloc).
The compounds of the present invention, as described in Formula I, show significantly improved growth inhibition of human transformed cell lines and/or cyclin/cdk inhibition relative to compounds of the prior art. These compounds have been demonstrated to be potent growth inhibitors in dozens of human transformed cell lines. Olomoucine, a structurally related purine derivative, is a poor human transformed cell growth inhibition agent with GI50 values in the 20,000-100,000 nM range over 60-transformed cell lines. By contrast, the compounds of the present invention demonstrate GI50 values over 60-transformed cell lines in the  less than 10-25,000 nM range, preferably in the  less than 10-100 nM range over 60-transformed cell lines, and, most preferably,  less than 10 nM across 60-human transformed cell lines. This finding is unexpected from the prior art, which specifically teaches that compounds of the present invention would not be potent human transformed cell line growth inhibitors.
The R2 group in Formula I imparts unexpected and significant improvement in growth inhibition in human transformed cell lines, while substitution of various groups at R3 and R4 found in Formula I impart important features that contribute to cyclin/cdk inhibition and growth inhibition of human transformed cell lines. Specifically, the combination of the R2 group and the substitutions within R3 and R4 result in compounds with superior biological activity. Compounds which are cyclin/cdk inhibitors and/or human transformed cell line growth inhibitors have utility in treating human proliferative cellular disorders.